ice were examined daily for neurological dysfunction and sacrificed on the day of onset of terminal clinical signs of scrapie. For transmission experiments, mice were inoculated ic with up 30 ml of 10% sonicated brain homogenate. Mice were monitored clinically every other day in order to ascertain the onset of clinical signs and the course of the disease. Clinical signs exacerbated over time and included progressive akinesia, priapism, hunchback, and stiff tail. Mice were sacrificed on the day of onset of terminal clinical signs of scrapie, defined as the time point at which they became unable to drink and/or eat. Supporting Information Acknowledgments We thank Ralph Schlapbach and the Functional Genomics Center Zurich for access to technologies, Christina Sigurdson for help with inoculations, Giuseppe Manco for technical assistance, and Carl Lagenaur for providing M6-7 antibody. Prion inoculations 812 weeks old mice were inoculated intracerebrally or intraperitoneally with 36106 infectious units or 106106 IU, respectively, of Rocky Mountain Laboratory strain is given to healthy human subjects. Lipopolysaccharide, a component of the outer cell membrane of gram-negative bacteria, induces its injurious effects by a non-cytotoxic interaction with CD14-bearing inflammatory cells, such as macrophage-monocytes, circulating neutrophils and lung epithelial cells. These effector cells are activated through a family of Toll-like receptors and subsequently release a network of inflammatory products. While we do not argue that the human endotoxin challenge model can precisely replicate an acute infectious or sepsis condition, we believe that human endotoxin challenge does serve as a useful model of TLR4 agonist-induced 
systemic inflammation while at the same time providing a reproducible experimental platform. The inflammatory response is a complex non-linear process involving a multi-scale cascade of events mediated by a large array of immune cells and inflammatory cytokines. At the cellular level, innate immune cells are activated resulting in the production and release of pro-inflammatory and anti-inflammatory MedChemExpress MK-2206 cytokines to the systemic circulation for cell communication. Antiinflammatory cytokines counteract the effects of pro-inflammatory cytokines and the relative concentration or balance between them strongly affects to the degree and extent of the response. At a higher level, the hypothalamic-pituitary-adrenal 10604956 axis and the sympathetic nervous system produces stress hormones whose pattern of release follow broad circadian rhythmicity which plays critical roles in immune 19632239 responses. This rhythmicity is regulated by the 24 hour light/dark cycle, exerting diurnal effects on numerous inflammatory cytokines. The complexity of the overall response has encouraged the development of mathematical and computational models as a means of exploring the connections between multiple components. Various modeling approaches have been proposed, but generally they can be classified into two main categories: equation-based and agent-based modeling. In previous Agent-Based Model of Human Endotoxemia studies, we developed a mathematical model of the human endotoxemia using equation-based modeling technique with ordinary differential equations . However, deterministic ODE models assume homogeneity and perfect mixing within compartments, while ignoring spatial effects. Given that stochasticity and heterogeneity have profound effects on the function of biological syst
